Polymorphisms in the TP53-MDM2-MDM4-axis in patients with rheumatoid arthritis

Background In addition to being a tumour suppressor, TP53 is a suppressor of inflammation, and dysfunction of this gene has been related to autoimmune diseases. Patients with autoimmunity, such as rheumatoid arthritis (RA) have an increased risk of certain cancers, like lymphomas, indicating that some underlying mechanisms may modulate risk of both cancers and autoimmunity. Methods We genotyped 5 common genetic variants in TP53 and its main regulators MDM2 and MDM4 in a sample of 942 RA patients and 3,747 healthy controls, and mined previously published GWAS-data, to assess the potential impact of these variants on risk of RA. Results For the TP53 Arg72Pro polymorphism (rs1042522), MDM4 SNP34091 (rs4245739) and MDM2 SNP285C (rs117039649), we found no association to risk of RA. For MDM2 SNP309 (rs2279744), the minor G-allele was associated with a reduced risk of RA (OR: 0.87; CI: 0.79–0.97). This association was also seen in genotype models (OR: 0.86; CI: 0.74–0.99 and OR: 0.79; CI 0.63–0.99; dominant and recessive model, respectively), but was not validated in a large GWAS data set. For MDM2 del1518 (rs3730485), the minor del-allele was associated with an increased risk of RA in the dominant model (OR: 1.18; CI: 1.02–1.38). Stratifying RA cases and controls into phylogenetic subgroups according to the combined genotypes of all three MDM2 polymorphism, we found individuals with the del158-285–309 genotype del/ins-G/G-T/T to have an increased risk of RA as compared to those with the ins/ins-G/G-G/G genotype (OR: 1.56; CI: 1.18–2.06) indicating opposite effects of the del1518 del-allele and the SNP309 G-allele. Conclusion We find a potential association between the MDM2 del1518 variant and RA, and indications that combinatorial genotypes and haplotypes in the MDM2 locus may be related to RA.publishedVersio

No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http:// creativecommons.org/licenses/by/4.0/.Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants. We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/ CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value.publishedVersio

Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date. In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/ CFS risk loci displaying genome-wide significance. In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 × 10− 7 ), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.publishedVersio

Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

The etiology and pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are unknown, and autoimmunity is one of many proposed underlying mechanisms. Human Leukocyte Antigen (HLA) associations are hallmarks of autoimmune disease, and have not been thoroughly investigated in a large ME/CFS patient cohort. We performed high resolution HLA -A, -B, -C, -DRB1, -DQB1 and -DPB1 genotyping by next generation sequencing in 426 adult, Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria. HLA associations were assessed by comparing to 4511 healthy and ethnically matched controls. Clinical information was collected through questionnaires completed by patients or relatives. We discovered two independent HLA associations, tagged by the alleles HLA-C*07:04 (OR 2.1 [95% CI 1.4–3.1]) and HLA-DQB1*03:03 (OR 1.5 [95% CI 1.1–2.0]). These alleles were carried by 7.7% and 12.7% of ME/CFS patients, respectively. The proportion of individuals carrying one or both of these alleles was 19.2% in the patient group and 12.2% in the control group (OR 1.7 [95% CI 1.3–2.2], pnc = 0.00003). ME/CFS is a complex disease, potentially with a substantial heterogeneity. We report novel HLA associations pointing toward the involvement of the immune system in ME/CFS pathogenesis.publishedVersio

Long-Term Use of Amoxicillin Is Associated with Changes in Gene Expression and DNA Methylation in Patients with Low Back Pain and Modic Changes

Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients (n = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study. Gene expression and DNA methylation were investigated at a genome-wide level at screening, after 100 days of treatment, and at one-year follow-up. We identified intra-individual longitudinal changes in gene expression and DNA methylation in patients receiving amoxicillin, while few changes were observed in patients receiving placebo. After 100 days of amoxicillin treatment, 28 genes were significantly differentially expressed, including the downregulation of 19 immunoglobulin genes. At one-year follow-up, the expression levels were still not completely restored. The significant changes in DNA methylation (n = 4548 CpGs) were mainly increased methylation levels between 100 days and one-year follow-up. Hence, the effects on gene expression occurred predominantly during treatment, while the effects on DNA methylation occurred after treatment. In conclusion, unrecognized side effects of long-term amoxicillin treatment were revealed, as alterations were observed in both gene expression and DNA methylation that lasted long after the end of treatment.publishedVersio

Multimodal human thymic profiling reveals trajectories and cellular milieu for T agonist selection

To prevent autoimmunity, thymocytes expressing self-reactive T cell receptors (TCRs) are negatively selected, however, divergence into tolerogenic, agonist selected lineages represent an alternative fate. As thymocyte development, selection, and lineage choices are dependent on spatial context and cell-to-cell interactions, we have performed Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and spatial transcriptomics on paediatric human thymu​​s. Thymocytes expressing markers of strong TCR signalling diverged from the conventional developmental trajectory prior to CD4+ or CD8+ lineage commitment, while markers of different agonist selected T cell populations (CD8αα(I), CD8αα(II), T(agonist), Treg(diff), and Treg) exhibited variable timing of induction. Expression profiles of chemokines and co-stimulatory molecules, together with spatial localisation, supported that dendritic cells, B cells, and stromal cells contribute to agonist selection, with different subsets influencing thymocytes at specific developmental stages within distinct spatial niches. Understanding factors influencing agonist T cells is needed to benefit from their immunoregulatory effects in clinical use

Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement

Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profiling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most inflammatory MC state. We found the expression of 37 genes significantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels significantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identified as significantly enriched among the upregulated genes in all three analyses. Our results point to inflammation and immunological defense as important players in MC biology in patients with chronic LBP.publishedVersio

Зависимость свойств толстопленочных терморезисторов от состава базовой шпинели

Изменением соотношения компонентов шпинели Cu1-x-yCo2yMn2-yO4 получены толстопленочные терморезисторы с удельным объемным электросопротивлением 1,5-33 Омм и тепловой константой В25/85 2980-3690 К

Accurate Adapter Information Is Crucial for Reproducibility and Reusability in Small RNA Seq Studies

A necessary pre-processing data analysis step is the removal of adapter sequences from the raw reads. While most adapter trimming tools require adapter sequence as an essential input, adapter information is often incomplete or missing. This can impact quantification of features, reproducibility of the study and might even lead to erroneous conclusions. Here, we provide examples to highlight the importance of specifying the adapter sequence by demonstrating the effect of using similar but different adapter sequences and identify additional potential sources of errors in the adapter trimming step. Finally, we propose solutions by which users can ensure their small RNA-seq data is fully annotated with adapter information